The main goal of this study is to identify molecules and biochemical cascades underlying pain modulation by the amygdala. The experiments in this proposal will test the hypothesis that the extracellular signal regulated kinase (ERK) cascade in the amygdala is involved in the modulation of pain sensation. My preliminary data shows strong activation of ERK in the central nucleus of the amygdala during the formalin test, a model of inflammatory pain in mice. To further characterize this observation, the proposed experiments will first examine the localization and levels of ERK activation in the amygdala at different time-points during the formalin test using western blot and immunohistochemical techniques. Next, the contribution of amygdala ERK activation to nociceptive behavior will be evaluated by blocking activation of ERK in the amygdala and measuring its effects on nociceptive responses to formalin. Intra-amygdala infusion of MEK inhibitors, which block activation of ERK, prior to the formalin test will be used for this aim. Finally, to further delineate the ERK signaling cascade in the amygdala, the metabotropic glutamate receptors (mGluRs) will be tested as candidate upstream activators of ERK. In this aim, agonists and antagonists of mGluRs will be infused into the amygdala prior to the formalin test. The effects of these drugs on nociceptive behavior and amygdala ERK activation will be measured. These studies will be the first to identify and characterize a specific biochemical cascade in the amygdala involved in the modulation of pain sensation. The results obtained will provide insights towards the development of new pharmacological agents to be used for pain management.